Manganese superoxide dismutase (MnSOD) is essential for the detoxification of intramitochondrially-generated superoxide. MnSOD deficient mice generated on the CD1 background quickly develop a dilated cardiomyopathy and metabolic acidosis and die within 10 days after birth. However, when the -/- mice were generated on a mixed genetic background of C57BL/6 and DBA/2J, an extended lifespan of up to 18 days was observed. Neuronal loss, rather than cardiomyopathy, appears to be the cause of death in the long-lived -/- mice. These findings indicate that genetic modifier(s) that can modulate the effects of high levels of intra-mitochondrial superoxide on the development of cardiomyopathy in the MnSOD deficient mice are present in certain strains of mice. The identification of these modifiers is of great importance in devising therapeutic approaches to the amelioration of free radical-induced mitochondrial damage and consequent tissue injury. Therefore, in Specific Aim I, genetic strategies will be used to localize these modifiers and to identify genetic markers closely linked to the modifier gene(s). The functions of the modifier alleles will then be studied in Specific Aim II by histological, biochemical and molecular approaches.